Keywords

Sudden death. Ions. Channelopathies. Ventricular fibrillation.

Abstract

First described in 1992, Brugada syndrome is characterized by a specific electrocardiographic pattern in the right precordial leads and susceptibility to ventricular arrhythmias and sudden death. Brugada syndrome is included among the channelopathies, primary electrical disorders that, characteristically, are not associated with concomitant structural cardiac abnormalities. In recent years, substantial preclinical and clinical research has led to the identification of multiple causative mutations and to understanding of the mechanisms underlying the development of the characteristic phenotype and of the factors that determine clinical prognosis in patients. Nevertheless, there remain numerous unresolved questions which provide an impetus for ongoing active research into the condition. This article provides a summary of what is currently known about Brugada syndrome and an overview of the principal preclinical and clinical studies that have made the most significant contributions to our understanding of the condition.

Article

INTRODUCTION

The syndrome of right bundle branch block,
ST segment elevation and sudden cardiac
death (SCD), better known today as Brugada
syndrome, was described in 1992 as a new clinical
and electrocardiographic syndrome involving
susceptibility to ventricular arrhythmias and SCD
in patients without obvious structural heart disease.1

The initial description, which included 8 patients,
was followed by reports of new isolated cases,2,3 and numerous studies soon appeared mainly aimed at
defining the clinical characteristics of larger series
of patients4,5 or the genetic, cellular and molecular
features of the disease.6-8 This review provides a summary of what is currently known about
Brugada syndrome and up-to-date information
from the main clinical and experimental studies
published in recent years.

DEFINITION AND EPIDEMIOLOGY

With more patients with Brugada syndrome
being identified, certain questions soon arose
regarding the definition of its characteristic
electrocardiographic (ECG) pattern and the
diagnostic criteria for the disease. Three different
ECG patterns were described (Figure 1)9:
a) type I, characterized by a coved-type ST-segment
elevation ≥2 mm in more than one right precordial
lead (V1-V3), followed by negative T waves; b) type II, characterized by ST-segment elevation ≥2 mm in right precordial leads followed by
positive or biphasic T waves, resulting in a saddle-back configuration; and c) type III, defined as any
of the 2 previous types if ST-segment elevation is ≤1 mm. Although the 3 patterns can be observed in Brugada syndrome, and even
in the same patient at different times,
type I is the only one that is considered
diagnostic of the disease, as specified in the
2 consensus documents published in 2002 and
2005.9,10 Both documents stated that the definitive
diagnosis of Brugada syndrome should only
be established when the type I ECG pattern is
documented in combination with at least one of the
following clinical criteria: documented ventricular
fibrillation (VF), documented polymorphic
ventricular tachycardia (VT), inducible ventricular
arrhythmias during electrophysiological study
(EPS), syncope or nocturnal agonal respiration,
a family history of SCD at <45 years of age, or
type I ECG pattern in other family members.9,10 Nevertheless, this definition today is becoming
outdated, particularly when we take into account
that other important aspects of the disease are
now known, such as causal mutations.11,12 In fact, our data demonstrate that a type I ECG pattern
alone, even when other clinical criteria are not
fulfilled, can be associated with SCD during follow-up.12 Thus, all patients who present a type I ECG
pattern, even when isolated, should be considered
at risk.

Figure 1. Electrocardiographic patterns (ECG) that can be found in the patients with Brugada syndrome. Type I only is diagnostic of the syndrome.

Brugada syndrome is included among the so-called channelopathies, that is, diseases produced
by alterations in the transmembrane ion channels
that participate in cell action potential, and which lead to an increased susceptibility to arrhythmias.
Channelopathies are purely electrical disorders and
are characteristically not associated with underlying
structural heart disease. In fact, Brugada syndrome
is the cause of 4% to 12% of all SCD and up to 20%
of SCD that occur in normal heart.10

The prevalence of Brugada syndrome has been
estimated at 5/10 000, although this figure possibly
underestimates the actual prevalence, since many
patients can present silent forms of the disease.
Great geographical variability has been reported,
such that the syndrome seems to be much more
frequent in Asia than in western Europe or North
America.13,14 In fact, the syndrome is thought to be endemic to certain regions of southeast Asia, where
it is usually known as sudden unexplained death
syndrome, also called bangungot (in Philippines),
pokkuri (in Japan), or lai tai (in Thailand).15

GENETIC FACTORS UNDERLYING BRUGADA
SYNDROME

Brugada syndrome is typically transmitted via
an autosomal dominant inheritance pattern.10 Nevertheless, the disease can be sporadic in a
significant proportion of patients, that is, absent
in other family members.16 The first mutations
associated with Brugada syndrome were found in
1998 in the SCN5A gene (locus 3p21), that encodes
for the cardiac sodium channel.6 To date, more than 100 different mutations leading to Brugada
syndrome have been described in the same gene,
whose effect, in all the cases studied, is a decrease
in transmembrane sodium current (INa), either
because of a quantitative reduction, or by a
qualitative channel dysfunction (Figure 2).7,15,17-20 Even though SCN5 A is the only gene to have been
associated with Brugada syndrome in almost a decade, only 18% to 30% of the patients test positive
for mutations in this gene, which indicates that the
disease is genetically heterogeneous.10 According
to this hypothesis, 4 new genes associated with
Brugada syndrome have been identified within the
last 2 years, although how much they contribute
to the total number of cases of the disease remains
unknown. The first of them, GPD1-L (glycerol-3-phosphate dehydrogenase 1-like),21 was described
by London et al in 2007, after having first identified
the causal locus (3p22-p24) in 2002.22 The authors demonstrated that the mutation A280V in GPD1-L indirectly led to sodium channel loss of
function, since it impaired the sodium channels
trafficking to the cell membrane.21 Perhaps more
novel is the finding of mutations in the CACNA1c
and CACNB2b genes that encode the calcium
channel23 and—quite recently—in the KCNE3 gene, that encodes for a b-subunit responsible for
the transient outward potassium currents (Ito).24 Functional studies have demonstrated that in these
cases, although the sodium channel is not affected,
Brugada syndrome phenotype can be explained
since a similar ion current imbalance occurs during
phase 1 of the action potential.

Figure 2. Examples of 2 SCN5A gene mutations that decrease the sodium currents by different mechanisms. A: mutation I1660V produces a trafficking
defect of the sodium channel to the cell surface; I, the wild-type channels (WT) are located both in the center and in the periphery; II, the channels with the
mutation I1660V remain trapped in the intracellular organelles, and are not trafficked to the cellular membrane; and III, the mutated channels can be rescued
by incubation at room temperature (modified by permission of Cordeiro et al18). B: mutation G1319V modifies the kinetic properties of the sodium channel;
I, maximal peak current amplitudes are similar in mutated cells and in WT, indicating that the number of functional channels is similar in both cases; II,
voltage-dependence of activation, showing a small depolarizing change in the mutated channels compared to WT; III, voltage-dependence of steady-state
inactivation, reflecting enhanced inactivation in mutant channels; and IV, recovery after inactivation, that seems markedly slower in the mutated channels
compared to WT (modified by permission of Casini et al19).

PATHOPHYSIOLOGY AND IONIC
AND CELLULAR MECHANISMS

Various experimental studies have enabled the
mechanisms involved in the development of the
2 main characteristics of Brugada syndrome to be
elucidated, namely: the typical ECG morphology,
and the susceptibility to VF and SCD. Figure 3
shows the normal action potential of ventricular
cardiomyocytes and the ion currents involved in
each of its phases. A decrease in INa, the disorder
more frequently observed in mutations in SCN5A
associated with Brugada syndrome,7,17-20 leads to an imbalance between the positive inward and
outward currents at the end of phase 1 of the cell
action potential. Figure 3 clearly shows that similar
situations occur when there is a decrease of the inward L-type calcium current (ICa(L)) (produced
by mutations in CACNA1c or CACNB2b)23 or an increase of the outward potassium currents (Ito)
(produced by the mutation recently described
in KCNE3).24 Whichever the mechanism, the
imbalance between the inward and outward currents
leads to the development of a characteristic notch
and the loss of the action potential dome mediated
by an increase (relative or absolute) of the outward
Ito currents. Since the density of Ito is greater in
epicardium than in endocardium, this event occurs
heterogeneously on the ventricular wall and leads
to a transmural voltage gradient, which produces
the characteristic ST-segment elevation in the ECG
(Figure 4).8

Figure 3.Transmembrane action
potential and ion currents that
participate in each of its phases. The
shaded area corresponds to phase
1, mainly determined by the balance
between the positive inward INa
and ICa(L) currents and the positive
outward Ito currents. When the
outward currents predominate over
inward currents (*), the cell undergoes
a certain degree of repolarization,
which produces the characteristic
notch in the action potential
(discontinuous line).

Figure 4.Proposed mechanism of ST-segment elevation in Brugada syndrome. The
appearance of a notch in certain regions of the epicardium, but not in the
endocardium, creates a transmural voltage gradient, which produces J-point
elevation. If the notch is marked, the action potential in the epicardium is
lengthened compared to the endocardium, which causes ST-segment elevation and
appearance of negative T-waves. Modified by permission of Antzelevitch.25
Endo indicates endocardium; Epi, epicardium; M, myocardium.

The ion current imbalance at the end of
phase 1 of the action potential also explains the
susceptibility to develop ventricular arrhythmias
in Brugada syndrome, which would arise via a
phase 2 reentry mechanism. In circumstances
where the notch reaches approximately -30 mV,
all-or-none repolarization occurs, which can
lead to the complete loss of the action potential
dome.25 This event also takes place heterogeneously
between the epicardium and endocardium and
even between various points in the epicardium,
leading to transmural and epicardial dispersion of
repolarization, respectively (Figure 5). This creates
a favorable substrate for the onset of premature ventricular complexes as a consequence of the
propagation of the action potential dome from
sites at which it is maintained to sites where it has
been lost (Figure 5B).8,25 This hypothesis has been
confirmed by high-resolution optical mapping
studies conducted in canine right ventricular
samples, which found a gradient between the
regions with and without a dome in the action
potential and the development of a reentrant circuit
initially limited to the epicardium that gradually
involved the endocardium (Figure 5C).26

Figura 5.
Proposed mechanism of ventricular arrhythmias in Brugada syndrome. A: a further shift in the balance of inward and outward currents at the
end of phase 1 produces all-or-none repolarization; in these circumstances the action potential dome can disappear completely (gray line), which causes
transmural (TDR) and epicardial (EDR) dispersion of repolarization (modified by permission of Antzelevitch25). B: action potentials recorded in endocardium
and in 2 epicardial sites in canine right ventricular samples; the administration of terfenadine, a sodium and calcium channel blocker, accentuates the
notch in the epicardial action potential and produces an all-or-none repolarization; this situation facilitates propagation of the action potential dome from
the regions where it is maintained to the regions that have lost it, which leads to a premature ventricular beat produced by a phase 2 reentry mechanism
(dashed arrows), that can trigger a polymorphic ventricular arrhythmia (modified by permission of Antzelevitch25). C: high-resolution optical mapping with
simultaneous registry of 256 action potentials in canine right ventricular samples; in line with the explanation offered in B, propagation can be observed from
regions indicated in red (that maintain the action potential dome) toward those in blue (without the action potential dome) (modified by permission of Shimizu
et al26).

The concept of an imbalance between inward
and outward ion currents, defining the pathological
substrate of Brugada syndrome, has many
applications. Firstly, it assists in the development
of experimental models of the disease, which can
be created via the administration of drugs that
open the outward potassium currents,8 sodium
channel blockers8 or combined sodium and calcium
channel blockers,27 among others. Furthermore,
it explains the effect of specific modulators and
certain special features of the syndrome, such as
increased phenotypic expression (and the risk of
arrhythmic complications) during vagal activity28-30 (acetylcholine blocks the calcium currents, whereas
betamimetics increase them),31 or the greater severity of the syndrome among men than in
women32 (men may have a constitutionally higher
density of Ito than women).33 On the other hand, maneuvers that increase ion imbalance are not
recommended for patients with Brugada syndrome,
such as the administration of sodium channel
blockers, although at the same time these drugs
may be useful in unmasking weakly expressed
forms of the syndrome (see section: Diagnostic
Tools: Drug Challenge Test).34 In contrast, drugs
with the opposite effect, therefore ones that restore
ion balance, could have an application in the
treatment of patients with Brugada syndrome. In
this regard, the first results have been obtained
using Ito blockers (such as quinidine)35 or ICa(L) activators (such as isoproterenol)36 (see section:
Treatment).

CLINICAL ChARACTERISTICS

Patients with Brugada syndrome usually remain
asymptomatic. Nevertheless, it has been reported
that 17% to 42% of them present syncope or SCD
as a consequence of a ventricular arrhythmia
at some time during their lives.37-40 This figure probably overestimates the real incidence of events,
given that many asymptomatic patients are not diagnosed. Patients usually present symptoms, especially SCD, during their fourth decade,16 although no conclusive explanation for this has
been offered to date (Figure 6). Approximately 23%
of the patients with SCD had already undergone
syncope.38

Figure 6. Incidence of sudden death
(SCD) or documented ventricular
fibrillation (VF) according to age at
presentation. Updated data of 370
patients taken from the international
registry. Cardiac events occurred in a
total of 120 patients (32.4%).

Given that a significant number of patients,
around 20%, may suffer supraventricular
arrhythmias, mainly atrial fibrillation (AF),41 some patients can experience palpitations and dizziness.
Other symptoms, such as neurally mediated
syncope, have also been reported in isolated cases
of Brugada syndrome.42,43

As occurs in other channelopathies with sodium
channel disorder, arrhythmias in Brugada syndrome
(and, thus, the symptoms) typically appear during
predominant vagal activity, such as rest, or even
during sleep.28 In a study by Matsuo et al,29 26 of
the 30 episodes of VF documented by automatic
implantable cardioverter-defibrillator (ICD)
occurred at night, which has been confirmed in more
recent series.30 As mentioned, increased vagal tone
mediated by acetylcholine decreases the calcium
currents, which could lead to arrhythmogenesis via
phase 2 reentry.31 On the other hand, a recent work
using positron emission tomography demonstrated
that the patients with Brugada syndrome present
a certain degree of sympathetic dysfunction, which
manifests as a decrease in norepinephrine at the
synaptic cleft, which also favors arrhythmogenesis
through a decrease in intracellular cyclic adenosine
monophosphate (AMP).44

The Brugada syndrome phenotype is thought
to be 8 to 10 times more prevalent in men than in
women.10 As proof of this, approximately 71% to
77% of patients diagnosed with Brugada syndrome
are men, a finding that is regularly observed in all
series.37-40 In a recent study that included a series of patients who were followed up for the longest
period to date, our group observed that, at the
time of diagnosis, men more frequently presented
previous symptoms and a spontaneous type I
ECG pattern and, in addition, developed greater
inducibility of VF during the EPS as compared to
women (Figure 7A).32 During follow-up, behavior
also differed according to sex. Of the 272 men
included in the study, 31 (11.6%) had documented
SCD or VF during an average follow-up period
of 58 (48) months, whereas the rate of events in
the female population during the same follow-up
period was considerably lower (3/112 [2.8%]; log-rank test P=.007) (Figure 7B).32

Figure 7.Differences in Brugada
syndrome patterns between men (M) and women (W). A: clinical
characteristics at the time of the
first clinical assessment. B: survival
analysis of major cardiac events
defined as sudden cardiac death
(SCD) or ventricular fibrillation (VF)
during follow-up. In total, 31/272 men (11.6%) and 3/212 women (2.8%)
presented major events during an
average follow-up of 58 months. Data
obtained from Benito et al.32

Two different hypotheses have been proposed to
explain why Brugada syndrome is more strongly
expressed in men than in women. On the one
hand, it has been demonstrated that there are
constitutional differences in the transmembrane
ion currents between sexes. In a study conducted
with canine samples, Di Diego et al33 verified that
the density of epicardial Ito currents is significantly
higher in men than in women,33 which, according to
the theory of ion imbalance in phase 1, predisposes
to greater ST-segment elevation and greater
susceptibility to the onset of ventricular arrhythmias (see section "Ion and Cellular Pathophysiology
and Mechanisms"). On the other hand, there are
suggestions that hormonal effects may play a role
in the phenotypical differences between sexes.
In this regard, disappearance of the ECG type
I pattern has been reported after castration in
patients with Brugada syndrome and concomitant
prostate cancer45 and, on the other hand,
testosterone concentrations seem to be significantly
greater in men with Brugada syndrome than in
controls.46 Some experimental studies suggest that hormones could exert their effect by modifying ion
currents.47,48 In line with the hormonal hypothesis, the current data, although sparse, on the pediatric
population with Brugada syndrome do not indicate
differences in behavior between boys and girls
before 16 years of age.49

In fact, although 3 of the 8 cases initially
published in the first description of the syndrome
were children, to date there has been little
information on the behavior of Brugada syndrome
in the pediatric population. Probst et al49 recently presented the results of 30 children less than
16 years of age included in a multicenter study.
More than half of the patients (n=17) had been
diagnosed during family screening, although
11 patients had already experienced symptoms.
They point out that, of the 11 symptomatic
patients, 10 had a spontaneous type I ECG pattern
and, characteristically, in 5 of them the symptoms
had appeared in association with febrile episodes.
An ICD was implanted in 5 patients and treatment
with hydroquinidine was begun in 4. During a mean
follow-up of 37 (12) months, 3 patients (10% of
the population) underwent SCD (n=1) or received
an appropriate ICD shock (n=2).49 The 3 patients
had previous syncope and all had a spontaneous
type I ECG pattern. It should be pointed out
that the 4 patients treated with hydroquinidine
remained asymptomatic throughout follow-up.49 We obtained similar results in population of
58 patients under 18 years of age.50 In our series, 6 patients presented major cardiac events (2 SCD
and 4 VF) during a mean follow-up of 48.8 (48)
months. Although cardiac events appeared more
often in the patients with a spontaneous ECG
type I pattern or inducibility during the EPS, the
presence of previous symptoms was the variable
most associated with prognosis in our pediatric
series (Figure 8).50 These 2 studies, although small,
indicate the following: a) Brugada syndrome may
manifest in the pediatric age group; b) febrile episodes are a frequent trigger of arrhythmias in
children with Brugada syndrome; c) symptomatic
patients, especially if presenting a spontaneous
ECG type I pattern, constitute a group with
particularly high risk of ventricular arrhythmias
within a relatively short follow-up period; and d) the patients with worse prognosis benefit from
ICD implantation, although quinidine treatment
may be proposed as an alternative, especially in the
youngest patients.

Figure 8. Survival analysis of major
cardiac events in the pediatric
population with Brugada syndrome.
Data obtained from 58 patients.50 The greater event rate was observed
among the symptomatic patients,
who in turn more frequently
presented a spontaneous Type I
electrocardiographic pattern and
inducibility of arrhythmias in the
electrophysiological study.

ELECTROCARDIOGRAM AND
MODULATING FACTORS

As mentioned, the only pattern which is definitive
and diagnostic of Brugada syndrome is a type
I ECG pattern (Figure 1). However, particular
clinical situations can lead to a similar ECG pattern
(Table 1). In some cases, this is due to completely
independent conditions which lead to ECG findings
resembling those of Brugada syndrome (thus,
these are conditions that should be ruled out in the
differential diagnosis), whereas in other cases ST-segment elevation is particularly evident when there
is a genetic predisposition.16

It is relevant to emphasize that the ECG of
patients with Brugada syndrome can vary over
time and, thus, can show type I, II, and III
patterns in a single patient at different times
or even be temporarily normal.51 Thus, serial electrocardiograms are recommended in all
patients.51,52 There are numerous modulating factors that to a certain extent may explain the
variability of the electrocardiogram. The factors
listed in the second column of Table 1 can
increase ST-segment elevation in the patients with
known Brugada syndrome, since they exacerbate
ion current imbalance during phase 1 of the
myocardial action potential.16,25,34 For the same reason, autonomic tone and the influence of certain
hormones can likewise modulate ST-segment
elevation and may even explain the greater rate of
occurrence of arrhythmias in particular conditions
(see section: Pathophysiology and Ion and Cellular
Mechanisms).28-30,45,46 Temperature can be an important modulating factor in some patients with
Brugada syndrome. It has been demonstrated
that, in some SCN5A mutations, a temperature
increase accentuates the premature inactivation of
the sodium channel.53 This explains why in some
patients febrile episodes can unmask silent forms
of Brugada syndrome and confer an increased risk
(transient) of ventricular arrhythmias,54,55 which seems to be especially important in the case of the
pediatric population.49

In recent years, numerous studies have attempted
to identify new characteristic ECG features and
their possible prognostic significance. Pitzalis
et al56 described a corrected QT interval (QTc)
prolongation in right precordial leads (but not
in left precordial leads) in patients with Brugada
syndrome, particularly after the administration of
sodium channel blockers. Subsequently, this was correlated with a worse prognosis, especially if the
duration of the QTc interval in V2 is ≥460 ms.57 Similarly, the aVR sign (defined as the presence
of an R wave ≥3 mm or a R/q ratio ≥0.75 in lead
aVR) has been associated with an increased risk
of ventricular arrhythmias (Figure 9A).58 In these cases, it is thought that the increase in the R wave
probably indicates greater ventricular conduction
delay and, thus, greater electrical heterogeneity.58 The presence of T-wave alternans, also a sign of
transmural dispersion of repolarization,59 can be observed in patients with Brugada syndrome after
the administration of sodium channel blockers
and, in addition, makes it possible to identify a
subgroup at greater risk of VF during follow-up (Figure 9B).60 On the other hand, and very
recently, it has been reported that up to 11% of the
patients with Brugada syndrome can present an
early repolarization pattern in inferior or lateral
leads, which is also associated with a greater rate of
symptoms (Figure 9C).61

Figure 9. Incidental electrocardiographic findings that have been
associated with a greater risk of
arrhythmias in patients with Brugada
syndrome. A: aVR sign (reproduced
by permission of Babai et al58). B: T-wave alternans, that can appear
after administration of sodium channel
blockers (modified by permission of
Tada et al60). C: early repolarization
pattern in inferior and lateral leads
(reproduced by permission of Sarkozy
et al61).

Conduction disorders can sometimes be observed
in the ECG of patients with Brugada syndrome.
In fact, the decrease in sodium currents can lead
to both phenotypes (Brugada syndrome and
conduction disorder), either in isolation or within
the same family.62 Thus, it has been reported that
parameters such as the PQ interval, the duration
of the QRS complex or the HV interval are more
prolonged in patients who have an identified
mutation in the SCN5A gene (and, thus, sodium
channel disorder) than in patients who test negative
for an SCN5A mutation.63 In a recent study with 200 patients with Brugada syndrome, our group
verified that certain conduction disorders, such
as prolonged QRS complex, are observed more
often among symptomatic patients than among
asymptomatic ones. In this population, a QRS
cut-off point of ≥120 ms effectively predicted an
odds ratio (OR) = 2.5 (95% confidence interval
[CI], 1.4-4.6; P=.003) of being symptomatic.64 It seems that women with Brugada syndrome are more susceptible to conduction disorders than
men.32 In fact, the administration of sodium
channel blockers during a challenge test in women
leads to a significantly greater increase in the PR
interval and QRS duration.32 This is in agreement
with the results of previous experimental studies
demonstrating that ventricular samples obtained
from canine females expressed a lower Ito current
those obtained from males, which explained the

predisposition to conduction disorders in the
former and, on the other hand, greater ST-segment
elevation in the latter.65

DIAGNOSTIC TOOLS: DRUG CHALLENGE
TEST

Given that the ECG pattern of patients with
Brugada syndrome varies over time and even can
be temporarily normal, the use of drug challenge
tests has grown in recent years. Sodium channel
blockers are the most often used drugs, mainly
because they are effective, easily available, and
have rapid activity.34 The administration regimens
of the main sodium blockers used as a diagnostic
test for Brugada syndrome are outlined in Table 2.10 Brugada syndrome is confirmed if, after testing
with any of these drugs, an ECG pattern defined as
type I (Figure 1) appears or is accentuated. The test
should be performed using continuous monitoring,
taking, an electrocardiogram every minute until the
end. It should be terminated when: a) type I ECG
pattern appears, thus confirming the diagnosis; b) multiple extrasystoles or other ventricular
arrhythmias appear; or c) QRS undergoes widening >130% compared to baseline.10

Current data indicate that ajmaline is the most
effective drug in the diagnosis of Brugada syndrome.
In a study with 147 individuals with an identified
SCN5A gene mutation, the drug challenge test
using ajmaline had a sensitivity, specificity, positive
predictive value and negative predictive value of
80%, 94.4%, 93.3%, and 82.9%, respectively, in the
diagnosis of Brugada syndrome.66 These figures
are considerably higher than those obtained using
flecainide in another study with 110 genotyped
patients, whose sensitivity, specificity, positive
predictive value and negative predictive value were
of 77%, 80%, 96%, and 36%, respectively.67 The low negative predictive value found in this study
is noteworthy, and should be taken into account
whenever a flecainide test is performed, especially
in particular contexts, such as in family screening.16 The diagnostic values of ajmaline and flecainide were directly compared in a recent study, in which
22 patients with confirmed Brugada syndrome
underwent successive challenge tests using the
2 drugs. Whereas the test confirmed the diagnosis
in all 22 patients when ajmaline was used, only
15 patients showed a positive test after flecainide
administration.68 Furthermore, ST-segment elevation
using ajmaline (0.43 [0.15] mV) was greater than
that obtained using flecainide (0.29 [0.18] mV).
Patch-clamp studies have verified that flecainide, in
addition to blocking the sodium channel, decreases
the Ito currents to a greater extent, which explains
its reduced effectiveness compared to ajmaline.68

Due to the limited value of the standard
electrocardiogram, even when facilitated by drug
challenge, new strategies have been proposed to help
in the diagnosis of Brugada syndrome. It has been
demonstrated that positioning the right precordial
leads in higher intercostal spaces (third and even
second intercostal space) increases sensitivity
in relation to the baseline electrocardiogram
and after administration of sodium channel
blockers.69 Recent data demonstrate that a type
I ECG pattern obtained in the second and third
intercostal spaces, even when the electrocardiogram
carried out with standard leads is normal, helps to
identify a subgroup of patients whose prognosis is
comparable to that of patients with a type I ECG
pattern in the standard leads (Figure 10).70 Thus, this strategy facilitates identifying patients at risk
who would not have been otherwise identified.

Figure 10.Survival analysis of
cardiac events (sudden death or
documented ventricular fibrillation)
in patients with a spontaneous
type I electrocardiographic pattern
obtained in standard leads, in
patients with spontaneous type I
electrocardiographic pattern which
only appears by raising the right
precordial leads to the second
or third intercostal space, and in
patients who develop a type I pattern
after administering sodium channel
blockers. No differences in prognosis
were found between the first 2 groups
(modified by permission of Miyamoto
et al70)

PROGNOSIS AND RISK STRATIFICATION

Due to the great phenotypic variability of
patients with Brugada syndrome, that ranges from
the absence of symptoms to SCD at an early age,
the search for parameters to help stratify risk has
been of great interest in recent years.37-40 However, the published studies have not obtained similar
results, and currently risk stratification in patients
with Brugada syndrome continues to be a matter of
debate in certain aspects.

In the last series presented by Brugada et al71 on the international registry database, the percentage
of individuals who had documented SCD or
VF at some time during their life was 25%
(178 of 724 patients). Undoubtedly, this figure
overestimates the real incidence of events, because,
on the one hand, this series included the first
patients identified in the first years after the disease
was described (usually the period when only the
clearest cases are identified) and, on the other,
because the population in the international registry
is usually at greater risk.16 However, in this series,
it is important to note that the incidence of major
events ranged between 3% and 45%, according to the baseline characteristics of the patients. This
justifies performing risk stratification in all patients
with Brugada syndrome.

Aborted SCD is an indisputable risk factor
and recognized by all studies.37-40 Data from Brugada et al37 confirm that, among patients
who have undergone aborted SCD, 62% present
a new arrhythmia during a mean period of 54
months. This means that these patients should be
protected with an ICD as secondary prevention
(class I indication).10 In patients without previous
cardiac arrest, Brugada et al reported that the
presence of previous syncope, a spontaneous type
I ECG pattern and the inducibility of ventricular
arrhythmias in the EPS are also prognostic markers.
In a population of 547 patients (mean age, 41 [45]
years; 408 men, 423 asymptomatic and 124 with
previous syncope; 71.5% with spontaneous type I
electrocardiogram at baseline), 45 individuals (8.2%)
presented a first major cardiac event (documented
SCD or VF) during a mean follow-up of 24 (32)
months.39 Univariate analysis associated a history
of previous syncope (hazard ratio [HR] = 2.79 [95%
CI, 1.5-5.1]; P=.002), the presence of a spontaneous
type I ECG pattern (HR=7.69 [95% CI, 1.9-33.3]; P=.0001), male sex (HR=5.26 [95% CI, 1.6-16.6]; P=.001) and the inducibility of ventricular
arrhythmias in the EPS (HR=8.33 [95% CI, 2.8-25]; P=.0001) with the appearance of events during
follow-up.39 Multivariate analysis confirmed the
presence of previous syncope and the inducibility
of VF in the EPS (Figure 11A) as independent
predictors of prognosis. Logistic regression analysis
assisted in defining 8 risk categories according
to the presence of symptoms, the findings of the baseline electrocardiogram, and the results of
the EPS (Figure 11B). Subsequent data analysis
identified the EPS as particularly useful in the
stratification of asymptomatic patients and without
a family history of SCD (known as fortuitous cases,
n=167). In fact, 11 of 167 patient (6%) presented
VF during follow-up and inducibility in the EPS
was the only factor associated with prognosis in this
subgroup of patients.71

Figure 11. Major cardiac events (sudden death or documented ventricular fibrillation) during follow-up of patients without previous cardiac arrest. A: event
survival analysis according to the presence of previous symptoms and inducibility of ventricular arrhythmias in the electrophysiological study. B: probability
of events during follow-up estimated by logistic regression analysis, according to the presence of symptoms, inducibility of arrhythmias and type of baseline
ECG (data obtained data from Brugada et al39).

Other groups agree that previous symptoms and
a spontaneous type I ECG pattern are risk markers
in patients with Brugada syndrome, although,
in general, they have reported a lower general
incidence of events (6.5% in the series of Priori et
al,38 with a mean follow-up of 34 [44] months, and 4.2% in the series of Eckardt et al,40 with a follow-up of 40 [50] months). This is probably due to
the fact that the series of Brugada et al included
populations of patients with more severe disease.40 The other groups also agree that the inducibility of
arrhythmias in the EPS is greater among patients
with syncope or MS38,40 but, in contrast to the series of Brugada et al, have not demonstrated
that the EPS has a role as a prognostic tool. There
may be several reasons to explain this difference:71a) the use of nonstandard ventricular stimulation
protocols due to including patients from several
centers; b) the inclusion, in some series, of patients
with a type II or type III ECG pattern, and thus,
without definite confirmation of the syndrome; and c) the absence of events during follow-up in the
other series. The last point may vary when longer
follow-ups are available, since events (and along
with them the positive predictive value) can only
increase with time.71

Since the first series were described, it has been
noted that Brugada syndrome appears in a more
aggressive form among men than among women.
Our group recently analyzed this observation in
384 patients (272 men and 112 women), recruited
from just 2 reference centers (Hospital Clínic de Barcelona, Barcelona, Spain and UZ Brussels,
Belgium) to avoid the selection bias that has
been attributed to the international database,
which mainly consists of high-risk patients.32 As mentioned, (see section: Clinical Characteristics),
men and women presented different baseline characteristics and a strikingly different behavior
during follow-up (Figure 7). This study also
contributed the new information that risk markers
could also be different between sexes.32 In fact, the
factors associated with poor prognosis described for
mixed populations (symptoms, spontaneous type
I ECG pattern and inducibility in the EPS) were
confirmed as valid for stratifying risk in men.32 In contrast, and taking into account the extremely low
event rate in the women, none of these variables
had sufficient power to identify those at greater
risk. In the female population, however, conduction
disorders seemed to be more associated with the
event rate, and the PR interval specifically was the
only independent predictor of risk in women.32

The presence of AF, which may be spontaneously
found in 10% to 54% of the patients with Brugada
syndrome,41,72 has recently been associated with
worse prognosis. In a series of 73 patients, Kusano
et al72 found that the patients with documented
spontaneous AF present a greater incidence of
syncope (60%) and documented VF (40%) than the
patients with no evidence of AF (22% and 14%,
respectively; P<.05). Our data indicate that this
is the case in the male population as well as in the
female population.32 As mentioned, other ECG
findings may have some prognostic significance,
among which are prolonged QTc interval in V2, the aVR sign, the presence of T-wave alternans,
a repolarization pattern in inferior or lateral
leads, and the width of the QRS complex (see
section "Electrocardiogram and Modulating
Factors").57-61,64

Neither a family background of SCD nor the
presence of SCN5A gene mutation have been
defined as risk factors in any of the large series
reported to date. However, recent studies indicate
that other genetic findings could well have
prognostic significance. In a study that included
147 patients with Brugada syndrome or progressive
conduction system disease, together carrying
32 different SCN5A gene mutations, Meregalli et
al73 reported that the patients carrying a mutation
resulting in premature stop codon (whose final
effect is the production of a truncated protein)
presented greater rates of syncope than the patients
carrying any other type of mutation (25.3% vs 5.7%,
respectively; P=.03). However, the authors could
not demonstrate differences in the rate of greater
arrhythmic complications (SCD or VF) according
to the type of mutation. Our data on 188 patients
(all with Brugada syndrome), together carrying
69 different SCN5A gene mutations, did in fact
demonstrate differences in the major events rate,
defined as SCD or VF at some time during their
lifetime (truncated mutation vs other mutations, 23.9% vs 7.7%; P=.01).74 On the other hand, it seems that the presence of certain polymorphisms
could modulate risk among patients with Brugada
syndrome. In this regard, we have observed that the
concomitant presence of the H558R polymorphism
and a SCN5A gene mutation is associated with
a more benign phenotype.75 In general, the search
for genetic parameters with prognostic value is
especially attractive, given that genetic information,
in contrast to clinical information, is constitutional
and, thus, invariant in the same individual.

TREATMENT

An ICD is the only treatment with demonstrated
efficacy in Brugada syndrome. The current
indications for ICD follow the recommendations
of the II International Consensus published in
200510 (Figure 12). In general, ICD implantation
is recommended for all patients who have already
had symptoms and for asymptomatic patients in
whom the EPS induces ventricular arrhythmias,
especially if they present a spontaneous type I ECG
pattern. In the asymptomatic patients, without
a family history of SCD and whose type I ECG
pattern is only documented after the administration
of sodium channel blockers, periodic follow-up is
recommended without the need of an EPS for risk
stratification.10

Taken together, the 2 main retrospective studies
conducted with patients with Brugada syndrome
implanted with an ICD show that the rate of
appropriate shocks is 3.7% per year.76,77 It should be noted that this rate is not only comparable to
that described in other studies conducted on other
heart diseases,78,79 but in this case it also refers to a young, and, furthermore, healthy population
whose life expectancy could be higher than
30 years. However, and possibly due to the fact that
a young active population was involved, the rate
of inappropriate shocks was considerable (20% in
the study of Sacher et al76 and 36% in the study of
Sarkozy et al77). The leading causes of inappropriate
therapy were, in both studies, sinus tachycardia,
supraventricular arrhythmias, T-wave oversensing
and lead failure.76,77 Thus, and because the ICD is not universally applicable therapy, in recent years
a special effort has been dedicated to searching for
possible drug options for the treatment of Brugada
syndrome.

With the aim of reducing the ion imbalance
at the end of phase I of the action potential,
2 main strategies have been proposed: a) the use
of potassium current (Ito) blockers, and b) the
use of drugs that increase the calcium (ICa(L))
currents. It has been demonstrated that quinidine,
an antiarrhythmic agent that blocks Ito currents,
reduces the incidence of induced arrhythmias in patients with Brugada syndrome,35 and it has been used successfully in specific clinical
situations, such as the treatment of arrhythmia
storms.80 Furthermore, its usefulness has recently
been demonstrated as adjunctive therapy to
ICD in patients with multiple shocks81 or as a therapeutic alternative to ICD in children at risk
of arrhythmias.49 In turn, betamimetic drugs, such
as isoproterenol, that increase inward ICa(L)
currents, have been used with good results in
cases of arrhythmia storm.36 Finally, the use of
cilostazol, a phosphodiesterase III inhibitor that
decreases Ito and increases ICa(L), has recently
emerged as a promising therapy, although the few
clinical cases published to date report inconsistent
results.16